ABSTRACT This K24 application is to provide support for protected time for: 1) mentoring/teaching of junior clinical investigators; and 2) patient-oriented research investigating the role of aldosterone in the pathophysiology of diabetic cardiovascular disease. Recent data provide support for the hypothesis that activation of the mineralocorticoid receptor (MR) contributes to diabetic vascular injury, though the mechanisms are uncertain. Consistent with this hypothesis, our pre-clinical studies demonstrate that blockade of MR reduces renal injury in diabetic db/db mice and reduces vascular inflammation and cardiac and renal injury in hypertensive, angiotensin II (ANGII)-infused rodents. Our clinical studies show that short-term treatment with the MR antagonist eplerenone improves coronary circulatory function as compared to treatment with hydrochlorothiazide (HCTZ) in subjects with diabetes receiving angiotensin-converting enzyme (ACE) inhibition therapy. This observation could not be attributed to blood pressure changes suggesting that MR antagonists are not working via a classical renal effect, but via an additional, volume control-independent mechanism. This proposal tests the hypotheses that MR activation contributes to progression of vascular disease in subjects with type 2 diabetes mellitus (T2DM) receiving ACE inhibitor therapy, and consequently, MR antagonists exert beneficial effects by reducing vascular dysfunction and injury, inhibiting ANGII vascular effects, improving coronary circulatory and cardiac function and improving renovascular function. To address these hypotheses we will perform a prospective double-blind study in subjects with T2DM and hypertension receiving chronic ACE inhibitor therapy randomized to one of three treatments: 1) MR antagonist spironolactone; 2) HCTZ plus potassium; and 3) placebo. These studies provide a fertile area for investigation by trainees interested in patient-oriented research and will provide new information about the mechanisms by which MR antagonists reduce diabetic cardiovascular injury, with the goal of introducing new, effective treatments of cardiovascular injury in individuals with diabetes.